single-enantiomer racemic drug pairs single-enantiomer FDA RCTs generic drugs

Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors: A Systematic Review

by Aaron S. Long, BS; Audrey D. Zhang, MD; Caitlin E. Meyer, MLIS; Alexander C. Egilman, BS; Joseph S. Ross, MD, MHS; Joshua D. Wallach, PhD, MS

May 6^th 2021
18 mins
JAMA Network Open. 2021;4(5):e215731

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Summary

Chiral Switching: A strategy where drug manufacturers develop a single-enantiomer formulation from a racemic one to extend market exclusivity, often without proving enhanced efficacy or safety.
Objective: To evaluate randomized clinical trials (RCTs) comparing FDA-approved single-enantiomer drugs with their racemic counterparts focusing on efficacy and safety.
Evidence Review: Utilized databases like Drugs@FDA and multiple research databases to identify and analyze trials. Trials were assessed based on the significance of primary and secondary efficacy and safety endpoints.
Findings:
- Identified 15 single-enantiomer drugs with racemic precursors. For 3 pairs, no direct RCTs were found.
- Out of 185 RCTs for 12 pairs, only 23 (12.8%) favored the single-enantiomer in efficacy, and 17 (13.7%) in safety.
- For 60% of the single-enantiomer drugs, no RCTs showed improved efficacy or safety over racemic precursors.
Conclusions and Relevance: Single-enantiomer drugs are rarely directly compared with racemic versions, and when compared, they seldom show superior efficacy or safety, despite higher costs.

In the US, a system of patents and market exclusivity provides manufacturers of new drugs protection against competition from generic drugs. Although this system balances higher prices from delayed generic competition with the need to promote new drug innovation, certain strategies, such as “chiral switching,” can allow manufacturers to maintain market exclusivity on drugs losing patent protection. Chiral drugs are made of mirror-image molecules called enantiomers (eg, a 50:50 racemic mixture of enantiomers), and in chiral switching, manufacturers develop a single-enantiomer drug that can be substituted for the already-approved racemic version (eg, escitalopram [(S)-citalopram] for citalopram [(R)- and (S)-citalopram]). Although manufacturers must submit a New Drug Application to the Food and Drug Administration (FDA) for these single-enantiomer formulations, concerns have been raised about whether these new drugs show sufficient evidence of superior efficacy or safety to justify their costs.

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